Trileptal (oxcarbazepine) tablets and oral suspension

WARNINGS AND PRECAUTIONS

Drug Reaction with Eosinophilia and Systemic Symptoms

(DRESS)/Multi-Organ Hypersensitivity

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multi-organ hypersensitivity, Has occurred with Trileptal. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Trileptal should be discontinued if an alternative etiology for the signs or symptoms cannot be established. Although there are no case reports to indicate cross sensitivity with other drugs that produce this syndrome, the experience amongst drugs associated with DRESS/multi-organ hypersensitivity would indicate this to be a possibility.

WARNINGS AND PRECAUTIONS

Serious Dermatological Reactions Association with HLA-B*1502

Patients carrying the HLA-B*1502 allele may be at increased risk for SJS/TEN with Trileptal treatment.

Human Leukocyte Antigen (HLA) allele B*1502 increases the risk for developing SJS/TEN in patients treated with carbamazepine. The chemical structure of Trileptal is similar to that of carbamazepine. Available clinical evidence, and data from nonclinical studies showing a direct interaction between Trileptal and HLA-B*1502 protein, suggest that the HLA-B*1502 allele may also increase the risk for SJS/TEN with Trileptal.

The frequency of HLA-B*1502 allele ranges from 2 to 12% in Han Chinese populations, is about 8% in Thai populations, and above 15% in the Philippines and in some Malaysian populations. Allele frequencies up to about 2% and 6% have been reported in Korea and India, respectively. The frequency of the HLA-B*1502 allele is negligible in people from European descent, several African populations, indigenous peoples of the Americas, Hispanic populations, and in Japanese (< 1%).

Testing for the presence of the HLA-B*1502 allele should be considered in patients with ancestry in genetically at-risk populations, prior to initiating treatment with Trileptal. The use of Trileptal should be avoided in patients positive for HLA-B*1502 unless the benefits clearly outweigh the risks. Consideration should also be given to avoid the use of other drugs associated with SJS/TEN in HLA-B*1502 positive patients, when alternative therapies are otherwise equally acceptable. Screening is not generally recommended in patients from populations in which the prevalence of HLAB*1502 is low, or in current Trileptal users, as the risk of SJS/TEN is largely confined to the first few months of therapy, regardless of HLA B*1502 status.

The use of HLA-B*1502 genotyping has important limitations and must never substitute for appropriate clinical vigilance and patient management. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been well characterized.